ABSTRACT
Suppression of bone marrow myeloid and erythroid progenitor cells occurs after infection with a variety of different viruses. In this study, we characterize the alterations in bone marrow (BM) lymphocytes after influenza virus infection in mice. We found a severe loss of BM B cells, particularly CD43(low/-)B220(+) pre-B and immature B cells, in influenza virus-infected mice. Depletion of BM B lineage cells resulted primarily from cell cycle arrest and most likely apoptosis within the BM environment, rather than from increased trafficking of BM emigrants to peripheral lymphoid tissues. Use of gene-knockout mice indicates that depletion of BM B cells is dependent on TNF-alpha, lymphotoxin-alpha, and both TNF receptors, TNFR1-p55 and TNFR2-p75. Thus, TNF-alpha and lymphotoxin-alpha are required for loss of BM B lineage cells during respiratory infection with influenza virus.
Subject(s)
Apoptosis/immunology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Lymphotoxin-alpha/metabolism , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Tumor Necrosis Factor-alpha/metabolism , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Base Sequence , Bone Marrow Cells/immunology , Bone Marrow Cells/pathology , Cell Cycle , Cell Differentiation , Killer Cells, Natural/immunology , Kinetics , Lymphotoxin-alpha/deficiency , Lymphotoxin-alpha/genetics , Macrophages, Alveolar/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae/pathogenicity , Orthomyxoviridae/physiology , Orthomyxoviridae Infections/virology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Tumor Necrosis Factor/deficiency , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/metabolism , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor-alpha/deficiency , Tumor Necrosis Factor-alpha/genetics , Virus ReplicationABSTRACT
To define the normal physiological role for the TRAIL/Apo2L in vivo, we generated TRAIL/Apo2L gene-targeted mice. These mice develop normally and show no defects in lymphoid or myeloid cell homeostasis or function. Although TRAIL/Apo2L kills transformed cells in vitro, TRAIL/Apo2L(-/-) mice do not spontaneously develop overt tumors at an early age. However, in the A20 B cell lymphoma-transferred tumor model, TRAIL/Apo2L(-/-) mice are clearly more susceptible to death from overwhelming tumor burden, due to increased lymphoma load in the liver. A20 tumors are susceptible to TRAIL/Apo2L killing in vitro, indicating that TRAIL/Apo2L may act directly to control A20 cells in vivo. Despite the fact that TRAIL binds osteoprotegerin and osteoprotegerin-transgenic mice are osteopetrotic, TRAIL/Apo2L(-/-) mice show no evidence of altered gross bone density, and no alterations in frequency or in vitro differentiation of bone marrow precursor osteoclasts. Moreover, leucine zipper TRAIL has no toxicity when repeatedly administered to osteoprotegerin(-/-) mice. Thus, TRAIL/Apo2L is important in controlling tumors in vivo, but is not an essential regulator of osteoprotegerin-mediated biology, under normal physiological conditions.